Wu R, Chen H, Ma J, He Q, Huang Q, Liu Q, Li M, Yuan Z
State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
Cell Death Differ. 2016 Mar;23(3):542-52. doi: 10.1038/cdd.2015.135. Epub 2015 Oct 30.
Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Abl-mediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD.
氧化应激是散发性帕金森病（PD）的主要病因。在此，我们证明了c-Abl在氧化应激诱导的神经元细胞死亡中起重要作用。c-Abl是一种非受体酪氨酸激酶，在1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐（MPTP）诱导的急性PD模型中被激活。在神经元中条件性敲除c-Abl或用c-Abl家族激酶抑制剂STI571处理小鼠，可减少多巴胺能神经元的损失，并改善短期MPTP处理诱导的运动缺陷。通过将细胞培养中氨基酸稳定同位素标记（SILAC）技术与其他生化方法相结合，我们在体外和体内确定p38α是c-Abl的主要底物，且c-Abl介导的磷酸化对p38α的二聚化至关重要。此外，抑制p38α可减轻MPTP诱导的多巴胺能神经元损失。综上所述，这些数据表明c-Abl-p38α信号通路可能是PD的一个治疗靶点。
